Cancer cells sense solid stress to enhance metastasis by CKAP4 phase separation-mediated microtubule branching
Abstract Solid stress, originating from rigid and elastic components of extracellular matrix and cells, is a typical physical hallmark of tumors. Mounting evidence indicates that elevated solid stress drives metastasis and affects prognosis. However, the molecular mechanism of how cancer cells sense...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-11-01
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| Series: | Cell Discovery |
| Online Access: | https://doi.org/10.1038/s41421-024-00737-1 |
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| author | Xing Sun Yangyang Zhou Shengjie Sun Siyuan Qiu Menglan Peng Han Gong Junxiao Guo Chengcai Wen Yibin Zhang Yifang Xie Hui Li Long Liang Guoyan Luo Wencan Wu Jing Liu Weihong Tan Mao Ye |
| author_facet | Xing Sun Yangyang Zhou Shengjie Sun Siyuan Qiu Menglan Peng Han Gong Junxiao Guo Chengcai Wen Yibin Zhang Yifang Xie Hui Li Long Liang Guoyan Luo Wencan Wu Jing Liu Weihong Tan Mao Ye |
| author_sort | Xing Sun |
| collection | DOAJ |
| description | Abstract Solid stress, originating from rigid and elastic components of extracellular matrix and cells, is a typical physical hallmark of tumors. Mounting evidence indicates that elevated solid stress drives metastasis and affects prognosis. However, the molecular mechanism of how cancer cells sense solid stress, thereby exacerbating malignancy, remains elusive. In this study, our clinical data suggest that elevated stress in metastatic solid tumors is highly associated with the expression of cytoskeleton-associated protein 4 (CKAP4). Intriguingly, CKAP4, as a sensitive intracellular mechanosensor, responds specifically to solid stress in a subset of studied tumor micro-environmental elements through liquid–liquid phase separation. These micron-scaled CKAP4 puncta adhere tightly onto microtubules and dramatically reorchestrate their curvature and branching to enhance cell spreading, which, as a result, boosts cancer cell motility and facilitates distant metastasis in vivo. Mechanistically, the intrinsically disordered region 1 (IDR1) of CKAP4 binds to microtubules, while IDR2 governs phase separation due to the Cav1.2-dependent calcium influx, which collectively remodels microtubules. These findings reveal an unprecedented mechanism of how cancer cells sense solid stress for cancer malignancy and bridge the gap between cancer physics and cancer cell biology. |
| format | Article |
| id | doaj-art-d582fd94c3034b45aead8efaecaefd49 |
| institution | Kabale University |
| issn | 2056-5968 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Discovery |
| spelling | doaj-art-d582fd94c3034b45aead8efaecaefd492024-11-17T12:09:22ZengNature Publishing GroupCell Discovery2056-59682024-11-0110111710.1038/s41421-024-00737-1Cancer cells sense solid stress to enhance metastasis by CKAP4 phase separation-mediated microtubule branchingXing Sun0Yangyang Zhou1Shengjie Sun2Siyuan Qiu3Menglan Peng4Han Gong5Junxiao Guo6Chengcai Wen7Yibin Zhang8Yifang Xie9Hui Li10Long Liang11Guoyan Luo12Wencan Wu13Jing Liu14Weihong Tan15Mao Ye16Department of Hematology, the Second Xiangya Hospital, Molecular Biology Research Center, Center for Medical Genetics, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South UniversityMolecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan UniversityDepartment of Hematology, the Second Xiangya Hospital, Molecular Biology Research Center, Center for Medical Genetics, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South UniversityDepartment of Hematology, the Second Xiangya Hospital, Molecular Biology Research Center, Center for Medical Genetics, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South UniversityMolecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan UniversityDepartment of Hematology, the Second Xiangya Hospital, Molecular Biology Research Center, Center for Medical Genetics, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South UniversityMolecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan UniversityDepartment of Hematology, the Second Xiangya Hospital, Molecular Biology Research Center, Center for Medical Genetics, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South UniversityDepartment of Hematology, the Second Xiangya Hospital, Molecular Biology Research Center, Center for Medical Genetics, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South UniversityDepartment of Hematology, the Second Xiangya Hospital, Molecular Biology Research Center, Center for Medical Genetics, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South UniversityDepartment of Hematology, the Second Xiangya Hospital, Molecular Biology Research Center, Center for Medical Genetics, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South UniversityDepartment of Hematology, the Second Xiangya Hospital, Molecular Biology Research Center, Center for Medical Genetics, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South UniversityHangzhou Institute of Medicine (HIM), The Chinese Academy of SciencesThe Eye Hospital of Wenzhou Medical UniversityDepartment of Hematology, the Second Xiangya Hospital, Molecular Biology Research Center, Center for Medical Genetics, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South UniversityMolecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan UniversityMolecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan UniversityAbstract Solid stress, originating from rigid and elastic components of extracellular matrix and cells, is a typical physical hallmark of tumors. Mounting evidence indicates that elevated solid stress drives metastasis and affects prognosis. However, the molecular mechanism of how cancer cells sense solid stress, thereby exacerbating malignancy, remains elusive. In this study, our clinical data suggest that elevated stress in metastatic solid tumors is highly associated with the expression of cytoskeleton-associated protein 4 (CKAP4). Intriguingly, CKAP4, as a sensitive intracellular mechanosensor, responds specifically to solid stress in a subset of studied tumor micro-environmental elements through liquid–liquid phase separation. These micron-scaled CKAP4 puncta adhere tightly onto microtubules and dramatically reorchestrate their curvature and branching to enhance cell spreading, which, as a result, boosts cancer cell motility and facilitates distant metastasis in vivo. Mechanistically, the intrinsically disordered region 1 (IDR1) of CKAP4 binds to microtubules, while IDR2 governs phase separation due to the Cav1.2-dependent calcium influx, which collectively remodels microtubules. These findings reveal an unprecedented mechanism of how cancer cells sense solid stress for cancer malignancy and bridge the gap between cancer physics and cancer cell biology.https://doi.org/10.1038/s41421-024-00737-1 |
| spellingShingle | Xing Sun Yangyang Zhou Shengjie Sun Siyuan Qiu Menglan Peng Han Gong Junxiao Guo Chengcai Wen Yibin Zhang Yifang Xie Hui Li Long Liang Guoyan Luo Wencan Wu Jing Liu Weihong Tan Mao Ye Cancer cells sense solid stress to enhance metastasis by CKAP4 phase separation-mediated microtubule branching Cell Discovery |
| title | Cancer cells sense solid stress to enhance metastasis by CKAP4 phase separation-mediated microtubule branching |
| title_full | Cancer cells sense solid stress to enhance metastasis by CKAP4 phase separation-mediated microtubule branching |
| title_fullStr | Cancer cells sense solid stress to enhance metastasis by CKAP4 phase separation-mediated microtubule branching |
| title_full_unstemmed | Cancer cells sense solid stress to enhance metastasis by CKAP4 phase separation-mediated microtubule branching |
| title_short | Cancer cells sense solid stress to enhance metastasis by CKAP4 phase separation-mediated microtubule branching |
| title_sort | cancer cells sense solid stress to enhance metastasis by ckap4 phase separation mediated microtubule branching |
| url | https://doi.org/10.1038/s41421-024-00737-1 |
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